Abstract

Cytochrome P450, named in the 1960s as a ‘chromatic (coloured) pigment in the cell’ having an absorption maximum of 450 nm
when reduced and bound to carbon monoxide, was originally thought to be a single enzyme. P450 was correlated with drug and
steroid metabolism; eventually, P450 was recognised to comprise an ancient gene superfamily encoding numerous ubiquitous enzymes
that participate in countless essential life processes. Almost 55 000 P450 genes have now been named across all kingdoms of
life. Nearly all eukaryotes require sterols in their membranes for essential fluidity and lipid‐packing properties; CYP51
(sterol 14α‐demethylase) synthesises these sterols and, therefore, is fundamental to eukaryotic life and most likely the ancestral
P450 gene from which all others were derived. Cytochromes P450 evolved novel functions in chordates, leading to the beginning
of steroid hormones. In conjunction with steroid hormone receptors, these novel regulatory pathways distinguish chordates
from other animals. Among human's 57 functional CYP genes, DNA variants can cause a number of inborn errors of metabolism,
other clinical diseases, and important differences in drug response.

Human CYP3A4 and CYP2D6 are the two major drug‐metabolising enzymes. Removal of mouse Cyp genes and replacement with their human CYP orthologous genes will lead to a better understanding of P450 metabolism that is relevant to clinical pharmacology.

Alterations in CYP drug metabolism are often responsible for adverse drug reactions – especially when multiple drugs are taken.

Triazole antifungal drugs (ketoconazole, fluconazole and itraconazole) target the CYP51 required for fungal sterol biosynthesis;
mutations in this gene can lead to triazole drug resistance.

Kelly SL and Kelly DE (2013) Microbial cytochromes P450: biodiversity and biotechnology. Where do cytochromes P450 come from, what do they do and what can they do for us? Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 368: 20120476.

Stiles AR, Kozlitina J, Thompson BM, et al. (2014) Genetic, anatomic, and clinical determinants of human serum sterol and vitamin D levels. Proceedings of the National Academy of Sciences of the United States of America 111: E4006–E4014.